Liposomal nanoparticles and other formulations of fenretinide for use in therapy and drug delivery
Inventors
Parchment, Ralph E. • Jasti, Bhaskara R. • Boinpally, Ramesh R. • Rose, Stephen E. • Holsapple, Earle T.
Assignees
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Publication Number
US-8709379-B2
Publication Date
2014-04-29
Expiration Date
Abstract
Formulations of neutral retinoids, in particular fenretinide (HPR) in the form of lipid nanoparticles, solid dispersions and emulsions are disclosed. These compositions are used to treat diseases that are amenable to treatment by HPR, such as neoplastic diseases by achieving higher and more prolonged concentrations of HPR in the subject. The key steps for preparing lipid nanovesicles of HPR include mixing and sonication, sterile filtration, without or without lyophilization for long-term stable storage, and employ processes and materials that are scalable from the laboratory to the manufacturing level. The formulation are suitable for injection into human or animal patients without causing allergic or hypersensitivity responses by avoiding chemical surfactants and animal sources of phospholipids in their manufacture.
Core Innovation
The invention relates to formulations and compositions for delivering a neutral retinoid, specifically fenretinide (HPR or N-4-hydroxyphenylretinamide, 4-HPR), using lipid nanovesicles and lipid nanoparticles, as well as emulsions and solid dispersions. The described problem is that fenretinide has poor aqueous solubility and limits of oral dosing, which constrain systemic exposure.
To address these limitations, the invention provides lipid nanoparticle compositions in which the neutral retinoid is integrated within a phospholipid component that is selected to avoid hypersensitivity-inducing excipients. The phospholipid component includes a plant lecithin acceptable for use in mammals in vivo and/or phospholipids and components such as cholic acid or a salt thereof together with synthetic chemically-defined phospholipids having two fatty acid chains.
The compositions are defined with nanoparticle size and surface charge characteristics to improve exposure, including nanoparticles having diameters of less than or equal to about 1000 nm and a zeta potential between about -50 millivolts and about +10 millivolts, together with retinoid integration to final retinoid concentrations between about 4 and about 75 mg/ml. The disclosed approach further supports higher and more prolonged systemic and tissue exposure with pancreas-selective accumulation, while excluding non-ionic surfactants and certain animal-derived lecithins.
In addition to lipid nanoparticles, the invention provides emulsion compositions that include a neutral retinoid in a hydrophilic and hydrophobic phase, with the hydrophobic phase dispersed as particles in a defined diameter range, and specific presence of ethanol and glycerin. The disclosed compositions are described as filterable through polycarbonate filters without substantially altering active retinoid or particle size range, supporting scalable pharmaceutical formulation characteristics.
Claims Coverage
The provided independent claims cover two formulation types: a lipid nanoparticle composition and an emulsion composition. Across these, the main inventive features comprise defined neutral retinoid integration/loading, defined particle size, specified phospholipid component selection, and defined surface charge or emulsion dispersion/filterability properties, with additional dependent claim refinements related to targeted pancreas accumulation and parenteral/exclusion constraints.
Lipid nanoparticle with integrated neutral retinoid in defined phospholipid component
Nanoparticles comprising a neutral retinoid integrated within a phospholipid component, wherein the nanoparticles have diameters less than or equal to about 1000 nm, the retinoid is integrated to a final retinoid concentration between about 4 and about 75 mg/ml, and the phospholipid component comprises a plant lecithin acceptable for use in mammals in vivo and/or phospholipids from said lecithin, or cholic acid (or a salt thereof) and one or more synthetic chemically-defined phospholipids having two fatty acid chains, or one or more synthetic chemically-defined phospholipids having two fatty acid chains.
Zeta potential constrained lipid nanoparticle surface charge
The nanoparticles have a surface charge characterized by a zeta potential between about -50 millivolts and about +10 millivolts.
Pancreas-selective accumulation after parenteral administration
After parenteral administration to a mammalian subject, the retinoid accumulates selectively in the pancreas with a pancreatic concentration at least four-fold higher than in plasma.
Emulsion with defined neutral retinoid amount and dispersed hydrophobic phase
An emulsion composition of a neutral retinoid comprising a hydrophilic and hydrophobic phase, having between about 4 and about 75 mg/ml of a neutral retinoid, and a plant lecithin or phospholipid components from said lecithin as a hydrophobic phase that confers hydrophobic-phase particles with diameters in the range of about 100 nm to about 5000 nm.
Filterable emulsion through polycarbonate filters without substantially altering retinoid or particle size range
The emulsion composition is filterable through polycarbonate filters with pore sizes ranging between 0.2 μm and 5 μm without substantially altering the amount of active retinoid or the particle size range.
Ethanol and glycerin specified for the emulsion
The emulsion composition comprises ethanol at a concentration between about 0.01 to about 10% v/v and glycerin at a concentration between about 5 and about 100 mg/ml.
Overall, claim coverage centers on formulation compositions that integrate a neutral retinoid into a defined phospholipid component at specified loading, control particle size and either nanoparticle zeta potential or emulsion dispersion and filterability, and provide biological distribution criteria for selective pancreas accumulation after parenteral administration.
Stated Advantages
Higher and more prolonged systemic and tissue exposure, including pancreas selective accumulation.
Pancreas-selective retinoid accumulation with pancreatic concentration at least four-fold higher than in plasma.
Formulations described as filterable through polycarbonate filters without substantially altering active retinoid or particle size range (for emulsion compositions).
Avoidance of hypersensitivity-inducing excipients by selecting plant lecithin acceptable for use in mammals in vivo and excluding non-ionic surfactants and certain animal-derived substances.
Documented Applications
Parenteral administration, including intravenous or other parenteral delivery to a human subject.
Topical formulations for skin precancers/cancers.
Use with biological evaluation in pancreatic tumor models (BXPC3 and PANC-1 xenografts) with reported tumor growth attenuation and retinoid selectivity for pancreas versus plasma.
Combination therapy context including Gemcitabine.
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